Project 3 An emerging problem for societies in developed countries is extending years of healthy life. Specialists in biology and genetics argue that major breakthrough in the field can be achieved by revealing genetic variants which can be involved in regulation of health in late life. A puzzling problem is that traits of late life are not the result of direct evolutionary selection that reinforces the role of life-course-related processes in an organism in heterogeneous environment which contribute to a complex spectrum of actions of genes on traits of late life. Analysis of the role of this complexity in genetic effects is not in mainstream of genome-wide association studies (GWAS). The objective of this subproject is to identify genetic underpinnings of major human diseases and related traits of late life using state-of-the-art methods addressing the role of life-course-related processes in an organism shaping genetic associations in heterogeneous environment and to dynamically integrate the revealed allelic variants into the individuals' health-related changes during life course. This challenging goal requires a rich data on the life course health-related processes assessed in the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), the Multi-Ethnic Study of Atherosclerosis (MESA), the Late Onset Alzheimer's Disease Family Study (LOADFS), the Health and Retirement Survey (HRS), and the Long Life Family Study (LLFS). Aim 1. Reveal genetic variants associated with quantitative phenotypes of physiological health given time-repeated observations for the same individuals using the FHS, ARIC, CHS, and MESA. Aim 2. Reveal genetic variants associated with risks of major human diseases using the FHS, ARIC, CHS, MESA, HRS, and LOADFS. Aim 3. Elucidate the role of the revealed allelic variants in lifespan and conduct dynamic integration. Aim 4. Dissect biological role of genes for the revealed SNPs and construct integrated variants. RELEVANCE (See instructions): This project directly addresses concerns which are of inherent relevance to public health including concern on genetic predisposition to medical complications and side-effects as a result of complex nature of gene action on health traits and concern on whether such genes can be considered as eariy life targets for preventive interventions as a result of their important role in health changes during the individuals' life course.